Bio-Inspired Drug Delivery Noting that platelets naturally migrate to narrowed blood vessels characterized by high fluid shear stress, Korin et al. (p. 738 , published online 5 July; see the Perspective by Lavik and Ustin ) developed a nanoparticle-based therapeutic that uses a similar targeting mechanism to deliver a drug to vessels obstructed by blood clots. Aggregates of nanoparticles coated with the clot-dissolving drug tPA (tissue plasminogen activator) were designed to fall apart and release the drug only when encountering high fluid shear stress. In preclinical models, the bio-inspired therapeutic dissolved clots and restored normal blood flow at lower doses than free tPA, suggesting that this localized delivery system may help reduce the risk of side effects such as excessive bleeding.

Skin, the largest organ in the body, protects against toxins and microorganisms in the environment and serves to prevent dehydration of all non-aquatic animals. Immune surveillance, sensory detection, and self-healing are other critical functions of the skin. Loss of skin integrity because of injury or illness may result acutely in substantial physiologic imbalance and ultimately in significant disability or even death. It is estimated that, in 1992, there were 35.2 million cases of significant skin loss (US data) that required major therapeutic intervention. Of these, approximately 7 million wounds become chronic. Regardless of the specific advanced wound care product, the ideal goal would be to regenerate tissues such that both the structural and functional properties of the wounded tissue are restored to the levels before injury. The advent of tissue-engineered skin replacements revolutionized the therapeutic potential for recalcitrant wounds and for wounds that are not amenable to primary closure. This article will introduce the reader to the field of tissue engineering, briefly review tissue-engineered skin replacement from a historical perspective and then review current state-of-the-art concepts from our vantage point.

Abstract-Cyclic mechanical strain produced by pulsatile blood flow regulates the orientation of endothelial cells lining blood vessels and influences critical processes such as angiogenesis. Mechanical stimulation of stretch-activated calcium channels is known to mediate this reorientation response; however, the molecular basis remains unknown. Here, we show that cyclically stretching capillary endothelial cells adherent to flexible extracellular matrix substrates activates mechanosensitive TRPV4 (transient receptor potential vanilloid 4) ion channels that, in turn, stimulate phosphatidylinositol 3-kinase-dependent activation and binding of additional ␤1 integrin receptors, which promotes cytoskeletal remodeling and cell reorientation. Inhibition of integrin activation using blocking antibodies and knock down of TRPV4 channels using specific small interfering RNA suppress strain-induced capillary cell reorientation. Thus, mechanical forces that physically deform extracellular matrix may guide capillary cell reorientation through a strain-dependent "integrin-to-integrin" signaling mechanism mediated by force-induced activation of mechanically gated TRPV4 ion channels on the cell surface. Key Words: mechanical strain Ⅲ integrin Ⅲ TRPV4 Ⅲ endothelial cell Ⅲ reorientation Ⅲ cytoskeleton M echanical forces regulate vascular growth and development by influencing endothelial cell growth, survival, differentiation and migration. 1,2 Local mechanical cues conveyed by extracellular matrix (ECM) attributable to cyclic deformation of blood vessels, hemodynamic forces, or cellgenerated traction forces are also potent inducers of directional capillary blood vessel growth and vascular remodeling in vitro and in vivo. [3][4][5][6][7][8][9][10] For example, the initial step in neovascularization involves reorientation of a subset of capillary endothelial (CE) cells that spread and migrate perpendicular to the main axis of the preexisting vessel toward the angiogenic stimulus 11 ; however, the molecular mechanism responsible for this CE cell reorientation response is unknown. Many cell types, including large vessel endothelial cells, realign perpendicular to the direction of the applied force when they experience cyclic stretching (mechanical strain). [12][13][14][15] In the case of macrovascular endothelium, this reorientation response can be prevented by treatment with chemical inhibitors of stretch-activated (SA) ion channels. 15 But neither the identity of these channels nor the mechanism by which they elicit cell reorientation is known.Endothelial cells express most members of the transient receptor potential (TRP) family of ion channels 16 -18 and TRP vanilloid (TRPV)4 has been reported to mediate flowinduced vasodilation in large vessel endothelium. 19 -22 Here, we show that calcium influx through TRPV4 channels stimulated by mechanically stretching CE cells through their integrin-extracellular matrix (ECM) adhesions promotes cell reorientation by activating phosphatidylinositol 3-kinase (PI3K), thereby stimulating activ...